PREDICT Sintesi della relazione

The research project PREDICT focuses on T lymphocytes, a cell type that is a key player in the immune system, controlling essentially all aspects of immune responses. The project aims at deciphering the T cell response that protects the host from infection by viruses, bacteria or fungi, but also that causes pathology when reacting against environmental antigens, such as in allergy, or self-antigens, such as in autoimmunity. The originality of the project resides in using several approaches for a global analysis of the human T cell repertoire, which is shaped as a consequence of the complexity of microbial and cellular signals as well as of environmental and genetic factors. The project is expected to provide answers to fundamental questions related to tolerance versus autoimmunity and new knowledge to design improved vaccines and therapeutic strategies. It aims also to define new clinical parameters related to disease state and severity, which are of primordial importance for diagnosis and therapeutic approaches of a disease. In the first 18 months of the project, we combined methods of next generation sequencing with in vitro stimulation and analysis of specific T cells, to establish for the first time a complete catalogue of the immune response to two important human pathogens, Candida albicans and Mycobacterium tuberculosis. Using this new approach, we could rapidly decipher the language of T lymphocytes, that is, their identity, specificity and function, and could do it for the thousands of clones that mediate the immune response against these pathogens. In this way we discovered that when a naive T cell recognizes a pathogen and proliferates in order to eradicate it, the progeny cells may undergo different fates, such as acquiring the ability to produce different types of cytokines or to migrate to different tissues. This extreme flexibility of T lymphocytes represents a new element that explains how the human immune system is able to respond to attacks with different weapons and on several fronts. We also discovered that patients with deficiency in the transcription factor RORγt and that suffer from candidiasis and mycobacteriosis have normal frequencies of T cells recognizing antigens from Candida albicans or Mycobacterium tuberculosis. However, these cells secreted much lower amount of interleukin-17 and interferon-γ, which are cytokines important to mediate protection against fungi and intracellular bacteria. Using a high-throughput T cell library method developed in the laboratory, we also studied the T cell response to non-pathogenic commensal microbes, in particular bacteria that reside in the nasopharynx and in the oral cavity, such as Streptococcus mites, as well as to environmental non-pathogenic Mycobacteria. Our results point to extensive intra- and inter-species cross-reactivity of T cells; for instance we found that Streptococcus mites-specific T cells recognize also pathogenic Streptococcus pneumoniae, while T cells specific for non-pathogenic Mycobacteria react also against pathogenic Mycobacterium tuberculosis. T cell response to commensals may also explain our finding of HIV-1–specific memory T cells in HIV-1–unexposed, seronegative donors. Taken together, these results, which have been obtained thanks to successful collaborations with several laboratories in Europe and USA, provide important insights into host–pathogen interactions and might offer insights in the design of vaccine candidates.